[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

CN102838550A - Quinolinylcrotyl compound and its application in preparation of anti-malignant tumor drugs - Google Patents

Quinolinylcrotyl compound and its application in preparation of anti-malignant tumor drugs Download PDF

Info

Publication number
CN102838550A
CN102838550A CN2012100785900A CN201210078590A CN102838550A CN 102838550 A CN102838550 A CN 102838550A CN 2012100785900 A CN2012100785900 A CN 2012100785900A CN 201210078590 A CN201210078590 A CN 201210078590A CN 102838550 A CN102838550 A CN 102838550A
Authority
CN
China
Prior art keywords
cancer
quinazoline
prodrug
metabolism
bolites
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
CN2012100785900A
Other languages
Chinese (zh)
Other versions
CN102838550B (en
Inventor
殷建明
朱惠霖
陶军华
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
HANGZHOU HUADONG MEDICINE GROUP NEW MEDICINE RESEARCH INSTITUTE CO., LTD.
Metabomics Inc.
Hangzhou Zhongmei Huadong Pharmaceutical Co Ltd
Original Assignee
METABOMICS Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by METABOMICS Inc filed Critical METABOMICS Inc
Priority to CN201210078590.0A priority Critical patent/CN102838550B/en
Publication of CN102838550A publication Critical patent/CN102838550A/en
Priority to PCT/CN2013/072528 priority patent/WO2013135176A1/en
Application granted granted Critical
Publication of CN102838550B publication Critical patent/CN102838550B/en
Active legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Images

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/94—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to a novel quinolinylcrotyl compound and its application in preparation of drugs preventing and/or treating anti-malignant tumors. The quinolinylcrotyl compound provided in the invention is an ideal high efficiency dual irreversible EGFR and HER2 kinase inhibitor, and can be used for treating or preventing breast cancer, ovarian cancer, gastrointestinal cancer, esophageal cancer, lung cancer, head and neck squamous cell carcinoma, pancreatic cancer, epidermal squamous cell carcinoma, prostate cancer, glioma and nasopharyngeal carcinoma and other malignant tumor diseases.

Description

Quinazoline crotonyl compounds and the purposes in the preparation anti-malignant tumor medicine thereof
Technical field
The present invention relates to the quinazoline crotonyl compounds and prevent and/or treat the purposes in the medicine of malignant tumour in preparation.
Background technology
(HER1/erbB1) one of molecule the most representative in the receptor type tyrosine kinase of film is striden to EGF-R ELISA by family, has biological function widely for epidermal growth factor receptor, EGFR.Multiple part such as Urogastron and transforminggrowthfactor-can combine with EGFR extracellular part, the mitotic division signal is transmitted in cell, thereby cell cycle regulation is regulated the cell normal differentiation, promotes injury repairing.But EGFR also the vascular epidermis growth factor receptors in its downstream of activation (vascular epidermal growth factor receptor VEGFR), promotes the solid tumor Capillary network to form.Therefore EGFR plays an important role in generation, development, differentiation, reparation and the transfer of tumour cell.Research shows, in the tumour in multiple epithelial cell such as mammary cancer, large bowel cancer, lung cancer, Head and Neck squama cancer and carcinoma of the pancreas source, all exists abnormal activation, amplification and the over-expresses of EGFR gene.A lot of with EGFR as the research of treatment target spot, wherein with its monoclonal antibody and tyrosine kinase inhibitor (tyrosine kinase inhibitor, TKI) successful.TKI acts on the EGFR cell interior, combines with ATP is competitive, suppresses kinase whose activity and phosphorylation, thereby and sealing EGFR SRCA TP binding site reach the purpose of specificity inhibition EGFR.
Human epidermal growth factor acceptor-2 (human epidermal growth factor receptor; HER2/neu; ErbB-2) be a transmembrane receptor; Over-expresses in many epidermis tumours such as mammary cancer, ovarian cancer, prostate cancer, nonsmall-cell lung cancer, nasopharyngeal carcinoma etc., there is the over-expresses of HER2/neu gene in about 25%～30% primary breast cancer.
Summary of the invention
Technical problem to be solved by this invention provides a kind of novel quinazoline crotonyl compounds; It is ideal EGFR and HER2 SU11752, can be used for effectively prevention or multiple malignancy diseases such as treatment mammary cancer, ovarian cancer, gastrointestinal cancer, the esophageal carcinoma, lung cancer, Head and Neck squama cancer, carcinoma of the pancreas, epidermis squama cancer, prostate cancer, neurospongioma and nasopharyngeal carcinoma.
For solving above technical problem, the present invention takes following technical scheme:
Quinazoline crotonyl compounds with general formula (I), its pharmacologically acceptable salt, hydrate, prodrug or the meta-bolites that forms of metabolism in any form,
Figure BDA0000146297980000021
Wherein:
R 1Be CH 2F, CHF 2, C 2～C 12The fluoro alkyl, C 2～C 12The chloro alkyl;
R 2, R 3Be hydrogen independently, C 1～C 12Alkyl;
Said quinazoline crotonyl compounds, its pharmacologically acceptable salt, hydrate with general formula (I), in the meta-bolites of prodrug or metabolism formation in any form, the hydrogen of non-exchangeability is not substituted, or is partly or entirely replaced by deuterium.
According to a preferred aspect of the present invention, R 1Be CHF 2, C 2～C 6Fluoro alkyl or C 2～C 6The chloro alkyl.Further preferably, R 1Be CHF 2Or C 2～C 3Fluoro alkyl, for example R 1Be CHF 2, CF 2CH 3, CF 2CH 2CH 3Or CHFCHFCH 3
R according to a further preferred aspect of the invention, 2, R 3Be C independently 1～C 6Saturated hydrocarbyl, more preferably C 1～C 3Saturated hydrocarbyl for example is methyl, ethyl or sec.-propyl.
Most preferably, shown in the structural formula as I a of The compounds of this invention:
Figure BDA0000146297980000022
According to the present invention; Described compound; It not only comprises single certain compound form, comprises that also multiple structure satisfies the form of mixtures of the compound that general formula (I) requires, and the different isomerization bodily form formula of same compound for example racemic modification, enantiomer, diastereomer etc.Described pharmacologically acceptable salt includes but not limited to hydrochloride, phosphoric acid salt, vitriol, acetate, PHENRAMINE MALEATE, mesylate, benzene sulfonate, benzoic acid salt, toluenesulfonate, SUMATRIPTAN SUCCINATE, fumarate, fumarate, tartrate, gallate, Citrate trianion etc.It is described that " prodrug with compound of general formula (I) " refers to a kind of material, after adopting appropriate means to use, can in subject, carry out metabolism or chemical reaction and be transformed at least a compound or its salt of structural formula (I).
According to the present invention, described " alkyl " except as otherwise noted, comprises aliphatic group and aryl radical, and wherein, aliphatic group can be straight chain, side chain or loop type.
The preparation of The compounds of this invention can be through the route of synthesis of well-known those the similar methods of chemical field, the synthetic compound of the present invention of description that particularly comprises according to this paper.Reagent generally obtains or is easy to use the well-known method preparation of those skilled in the art from commercial source.
Because the enforcement of above technical scheme, the present invention compared with prior art has following advantage:
Compound provided by the invention is novel quinazoline crotonyl compounds; It is the efficient dual non reversibility tyrosine kinase inhibitor of ideal; Combine with ATP is competitive through acting on the EGFR intracellular portion; Suppress kinase whose activity and phosphorylation, thereby and sealing EGFR SRCA TP binding site reach the purpose that specificity suppresses EGFR.Therefore The compounds of this invention can be used for preparing treatment or prevents the various indications relevant with the HER2 kinase function with EGFR, includes but not limited to multiple malignancy diseases such as mammary cancer, ovarian cancer, gastrointestinal cancer, the esophageal carcinoma, lung cancer, Head and Neck squama cancer, carcinoma of the pancreas, epidermis squama cancer, prostate cancer, neurospongioma and nasopharyngeal carcinoma.
Description of drawings
Fig. 1 is compound I a suppresses test to the kinase whose non-reversibility of EGFR figure as a result;
Fig. 2 is that compound I a is at nude mice H1975 tumour cell heteroplastic transplantation model figure;
Fig. 3 is the compound I a graph of a relation that plasma concentration versus time changes in nude mice.
Embodiment
Below in conjunction with specific embodiment the present invention is done further detailed explanation, but the present invention is not limited to following examples.The compound title that below provides for reference only is as the criterion with structural formula of compound.
Embodiment 1
Compound 1a, its chemical name is: N-[4-[(3-chloro-4-fluorophenyl) amino]-7-(difluoro-methoxy)-6-quinazolyl]-4-(dimethylamino)-2-butylene acid amides, its chemical structural formula is following:
Figure BDA0000146297980000031
Compound I a can obtain through following synthetic route:
The preparation method of compound I a specifically comprises the steps:
1., preparation midbody 6: with 7-chloro-4-hydroxyl quinazoline is starting raw material, uses sulfuric acid and concentrated nitric acid nitrogenize to obtain midbody 7 [hydrogen nuclear magnetic resonances 1H NMR (400MHz, D 6-DMSO) absorption peak: δ 8.61 in the spectrogram (s, 1H), 8.27 (s, 1H), 7.94 (s, 1H).Mass spectrum m/s: [MH] +: 226.0].Then at room temperature, (75g 1.39mol) slowly stirs and is added to midbody 7 (50g is 221.6mmol) in DMSO (1000ml) solution with sodium methylate.After stirring reaction 1-2 hour, thin up transfers to pH5-6 with concentrated hydrochloric acid, filtering-depositing, and drying obtains midbody 6 (40g, 81.6%) [hydrogen nuclear magnetic resonance 1H NMR (400MHz, D 6-DMSO) absorption peak: δ 12.50 in the spectrogram (s, 1H), 8.50 (s, 1H), 8.22 (s, 1H), 7.40 (s, 1H), 4.04 (s, 3H).Mass spectrum m/s: [MH] +: 222.1].
2., preparation midbody 3: use lithium chloride and 18 crown ether-6 reflux demethyl to obtain midbody 5 [hydrogen nuclear magnetic resonances 1H NMR (400MHz, D 6-DMSO) absorption peak: δ 12.32 in the spectrogram (s, 1H), 11.89 (s, 1H), 8.52 (s, 1H), 8.13 (s, 1H), 7.20 (s, 1H).Mass spectrum m/s: [MH] +: 208.1].Then at room temperature, (74.6g 540.9mmol) stirs and to be added to midbody 5 (45g is 216.3mmol) in DMF (1000ml) solution with salt of wormwood.And then in reaction solution, add successively the difluoro Mono Chloro Acetic Acid (70.6g, 45ml, 540.9mmol), cesium carbonate (70.5g, 216.3mmol), 18 crown ether-6 (4.5g, 17mmol) and Pottasium Hydroxide (24.2g, 432.7mmol).Reacting by heating liquid to 90 ℃, stirring reaction 1 hour.Thin up transfers to pH4-5, uses ethyl acetate extraction again.Organic phase is washed with saturated nacl aqueous solution, anhydrous sodium sulfate drying, and filtering and concentrating and in vacuum-drying, the silicagel column purifying obtains midbody 4 (17g, 30.5%) [hydrogen nuclear magnetic resonance 1H NMR (400MHz, D 6-DMSO) absorption peak: δ 10.39 in the spectrogram (s, 1H), 9.43 (s, 1H), 8.76 (s, 1H), 8.17-8.15 (dd, 1H), 7.80 (s, 1H), 7.79-7.40 (t, j=72Hz, 1H), 7.76 (s, 1H), 7.51-7.47 (t, 1H).Mass spectrum m/s: [MH] +: 258.1].With POCl3 midbody 4 is carried out chlorination reaction at last and obtain midbody 3, and be used for next step reaction immediately.
3., preparation midbody 2: at room temperature, (9.6g 66.1mmol) stirs and to be added to midbody 3 (18.1g is 66.1mmol) in THF (20ml) solution with 3-chloro-4-fluoroaniline.And then in reaction solution, add triethylamine (9.2ml, 66.1mmol), stirring reaction is after 30 minutes under the room temperature, thin up is used ethyl acetate extraction again.Organic phase is successively with the flushing of 1N hydrochloric acid and saturated nacl aqueous solution, anhydrous sodium sulfate drying, and filtering and concentrating and in vacuum-drying, the silicagel column purifying obtains midbody 2 (9g, 35.4%).[ 1H NMR (400MHz, D 6-DMSO) absorption peak: δ 10.39 in the spectrogram (s, 1H), 9.43 (s, 1H), 8.81 (s, 1H), 8.17-8.15 (dd, 1H), 7.79-7.45 (t, j=68.8Hz, 1H), 7.81 (s, 1H), 7.73 (s, 1H), 7.56-7.49 (s, 1H).Mass spectrum m/s: [MH] +: 385.7].
4., preparation midbody 1: at room temperature, Raney's nickel (500mg) slowly is added to midbody 2, and (5g is 13.0mmol) in ETHYLE ACETATE (100ml) solution.Stirring reaction is 12 hours under hydrogen environment.Filtering and concentrating also obtains midbody 1 (thick product 4.5g, 97.8%) [mass spectrum m/s: [MH] in vacuum-drying +: 355.2].This midbody 1 thick product directly is used for next step reaction.
5., preparation midbody 1b:
Midbody 1b can obtain through following synthetic route:
Figure BDA0000146297980000051
Concrete preparation process is following:
Under 0 ℃, (3.5g, (3.5g is in tetrahydrofuran solution 21.2mmol) (30ml) 27.6mmol) slowly to be added drop-wise to trans-4-dimethyl amido cronate hydrochlorate with oxalyl chloride while stirring.Reaction solution slowly is warmed up to normal temperature, stirring reaction 3 hours.Concentrate and obtain midbody 1b and be used for next step reaction immediately.
6., preparation compound I a: under 0 ℃, while stirring with midbody 1b (3.9g, anhydrous tetrahydrofuran solution 21.2mmol) (10ml) slowly be added drop-wise to midbody 1 (4g, 11.3mmol) in.Reaction solution slowly is raised to normal temperature, stirring reaction 3 hours.Stop and diluting reaction with saturated sodium bicarbonate then, use ethyl acetate extraction again.Organic phase is washed with saturated nacl aqueous solution, anhydrous sodium sulfate drying, and filtering and concentrating and in vacuum-drying, the silicagel column purifying obtains target product (2g, 38%) with the acetonitrile recrystallization then.
Target product compound I a to obtaining has carried out hydrogen nuclear magnetic resonance 1H-NMR (400MHz, CD 3OD) and mass spectrometric measurement, the result is following:
1Absorption peak in the H-NMR spectrogram: δ 8.91 (s, 1H), 8.51 (s, 1H), 8.03-8.01 (dd, 1H); 7.68-7.61 (dd, 1H), 7.50 (s, 1H), 7.33-6.97 (t, j=72Hz; 1H), and 7.26-7.22 (t, 1H), 7.06-6.99 (m, 1H), 6.52-6.49 (d; 1H), 3.30-3.21 (d, 2H), 3.32 (s, 6H).
m/s：[MH] +：466.2。Calculate product and have molecular formula C 21H 19ClF 3N 5O 2, accurately molecular mass (exact mass) is 465.12.
The test of pesticide effectiveness, pharmacokinetics and toxicology test
One, compound enzymic activity test:
1, TP
The 503nhibiting concentration IC of compound 50(suppressing enzymic activity to 50% o'clock required compound concentrations) is to measure with the testing compound of fixed enzyme mixing specific substrates and different concns.Used measuring method is slide calliper rule migration variation analysis (Caliper Mobility Shift Assay), and the kinases of being measured is EGFR WTAnd HER2, and the EGFR kinases of mutant, comprise single mutation type EGFR L858R, EGFR T790MWith two mutant egf R L858R/T790MApplied standard reference compound is Staurosporine (staurosporine).
2, test-results
Table 1 has been summed up the compound enzymic activity and has been suppressed experimental result.The result shows that compound I a is to EGFR WTHas very strong restraining effect with the HER2 kinases.It should be noted that the EGFR kinases of compound I a especially, comprise single mutation type EGFR mutant L858R, EGFR T790MWith two mutant egf R L858R/T790MAlso has very strong restraining effect.
Table 1 compound I a suppresses experimental result to multiple kinase activity
Figure BDA0000146297980000061
Figure BDA0000146297980000071
Simultaneously, also verified that through molecular biology method EGFR suppressor factor new compound can EGFR intracellular portion and ATP are competitive to be combined through acting on, thereby and the form through covalent linkage combine to reach its non-reversibility characteristic.Referring to Fig. 1, the reversible restraining effect test result of EGFR kinase enzymatic activity shows that compound I a has the characteristic of non-reversibility.
Two, tumour cell inhibition test:
1, TP
(1), compound: earlier compound I a is dissolved among the 100%DMSO in the in vitro study, redilution is to desired concn, and the final concentration of DMSO is 0.1%.The DMSO of 0.1% (v/v) is added substratum as solvent control, totally 9 concentration gradients, repeated test secondary.
(2), tumor cell line: the tumour cell of surveying ties up in RPMI1 0 substratum that contains 10% foetal calf serum, in 5%CO 2, cultivate in 37 ℃ of incubators.The tumor cell line of surveying is: BT474, MDA-MB-231 and SK-Br-3 (breast cancer tumour cell), A431 (dermatoma cell), H292, H1781, H1975, Hcc827, H1666, A549, H1650 and H1734 (nonsmall-cell lung cancer tumour cell).
(3), the MTS method: cell inoculation in 96 orifice plates, 3000 cells in every hole, and at 5%CO 2, incubated overnight in 37 ℃ of humidification incubators.After adding test compounds in the hand-hole in second day, hatched again 72 hours.Use MTS to detect cell activity.Calculate IC 50(compare to make the cell growth receive 50% suppress required drug level, use the nonlinear regression analysis of GraphPad Prism software to calculate) with the DMSO control group.
2, test-results
Compound I a suppresses activity to BT474, MDA-MB-231, SK-Br-3, A431, H292, H1975, Hcc827, A549, H1650 and H1734 tumour cell and is summarised in the table 2.
Table 2 tumour cell inhibition test result
Tumor cell line IC 50(μM)
A431 0.652
BT474 0.034
H292 2.65
H1975 0.80
Hcc827 0.002
MDA-MB-231 Greater than 10000
SK-Br-3 0.23
A549 3.722
H1650 3.238
H1734 0.539
Visible from table 2; The compounds of this invention Ia has all showed significant inhibition activity to various tumour cells (BT474, SK-Br-3, A431, H292, H1975, Hcc827, A549, H1650 and H1734), and wherein H1975, A549, H1650 and H1734 are the tumor cell line of ZD1939 and the anti-Types of Medicine of erlotinib.
Three, the restraining effect of people's nonsmall-cell lung cancer tumour cell transplanted tumor in nude mice test
1, TP: 18 of nude mices (BALB/c, female, age in 5-6 week), inoculation H1975 people nonsmall-cell lung cancer tumour cell treats that the knurl average-volume reaches 150mm 3The time, be divided into 3 groups at random, be respectively control group (5 nude mices), 20mg/kg/ days compound I a dose groups (8 nude mices) and 75mg/kg/ days ZD1939 dose groups (5 nude mices), successive administration 21 days, oral administration.Write down the big or small and nude mice body weight of tumour weekly twice from medication treatment beginning in first day.With formula (l * w 2)/the calculate weight of tumour, the wherein each minimum and maximum size of measuring of l and w representative.Draw the graph of a relation that the fate of tumor average volume after with tumour transplatation changes respectively according to result calculated.
2, result: referring to Fig. 2; The test of people's nonsmall-cell lung cancer tumour cell transplanted tumor in nude mice shows that The compounds of this invention Ia shows better therapeutic effect to nonsmall-cell lung cancer H1975 tumour tumor model, has suppressed the growth (T/C% is 59%) of H1975 cell.And ZD1939 is to the readily good therapeutic effect of nude mice H1975 tumor model, and its H1975 cell speed of growth and control group are similar.
Four, pharmacokinetic experiment
1, experimental technique:
Laboratory animal: BALB/c nude mice, female, 5～6 weeks; Body weight: 20～25g;
Trial-product preparation: with compound I a be mixed with 0.6mg/mL (for intravenously administrable with) and the solution of 1.5mg/mL (for oral administration usefulness), for use.Route of administration: oral/vein.Administration capacity and frequency: 10mL/kg, single-dose.
Sample collecting: adopt the heart puncturing extracting blood method after the Animal Anesthesia, gather blood according to following time point, 3 animals of each time point are got the about 0.5-1.0mL of whole blood.5min, 15min, 30min, 1h, 2h, 4h, 8h and 24h get blood after administration.
2, sample analysis and result
Sample analysis: use the LC-MS/MS method that collected specimens is detected.Use the instrument model to be SHIMADZU20A-API4000.
Pharmacokinetics data analysis: use WinNolin gained Plasma Concentration data to be carried out match and calculating according to non-compartment model method.See Fig. 3 according to Plasma Concentration and time history, the bioavailability of computerized compound Ia in the BALB/c nude mice is 45.2%.
Test-results in the BALB/c nude mice shows that The compounds of this invention has the excellent drug dynamic characteristic, comprises that clearance rate is low, oral absorption good, long half time and higher attributes such as tissue distribution.
Five, other experiments
Compound I a is at CD1 mouse toxicological test (25mg/kg; QD x 5 days) and rat toxicological test (15mg/kg; QD x 14 days) in, during whole test, do not find any animal dead, main clinic symptoms is that the hair filth of tail of the eye place appears in administration group part animal; And become thin symptoms such as the back of a bow, soft stool.At duration of test, each is organized body weight and presents rising tendency substantially.The food ration of animal is about the same in each group food ration.Cut open inspection final period and do not find that main organs has the significantly substantially variation relevant with administration.Hematology detects the neutrophil leucocyte and the monocyte that show compound I a administration group and all occurs raising.Serum biochemistry is learned detected result and is shown that comparing compound I a administration group with control group does not find considerable change.
Above embodiment only is representational.Visible through the foregoing description; Compound of the present invention is the efficient dual non reversibility tyrosine kinase inhibitor of ideal; Can expect to be used for multiple malignancy diseases such as treatment or Breast Cancer Prevention, ovarian cancer, gastrointestinal cancer, the esophageal carcinoma, lung cancer, Head and Neck squama cancer, carcinoma of the pancreas, epidermis squama cancer, prostate cancer, neurospongioma and nasopharyngeal carcinoma and obtain extraordinary effect, it can also combine with dissimilar pharmaceutical salts and process oral prepns (tablet or capsule etc.).The tablet of processing with The compounds of this invention or capsule can be taken once a day or repeatedly.The compounds of this invention also can combine to process compound preparation with other its medicines.
The foregoing description only is explanation technical conceive of the present invention and characteristics, and its purpose is to let the personage who is familiar with this technology can understand content of the present invention and enforcement according to this, can not limit protection scope of the present invention with this.All equivalences that spirit is done according to the present invention change or modify, and all should be encompassed within protection scope of the present invention.

Claims (10)

1. the quinazoline crotonyl compounds that has general formula (I), its pharmacologically acceptable salt, hydrate, prodrug or the meta-bolites that forms of metabolism in any form,
Figure FDA0000146297970000011
Wherein:
R 1Be CH 2F, CHF 2, C 2～C 12The fluoro alkyl, C 2～C 12The chloro alkyl;
R 2, R 3Be hydrogen independently, C 1～C 12Alkyl;
Said quinazoline crotonyl compounds, its pharmacologically acceptable salt, hydrate with general formula (I), in the meta-bolites of prodrug or metabolism formation in any form, the hydrogen of non-exchangeability is not substituted, or is partly or entirely replaced by deuterium.
2. the quinazoline crotonyl compounds with general formula (I) according to claim 1, its pharmacologically acceptable salt, hydrate, prodrug or the meta-bolites that forms of metabolism in any form is characterized in that: R 1Be CHF 2, C 2～C 6Fluoro alkyl or C 2～C 6The chloro alkyl.
3. the quinazoline crotonyl compounds with general formula (I) according to claim 2, its pharmacologically acceptable salt, hydrate, prodrug or the meta-bolites that forms of metabolism in any form is characterized in that: R 1Be CHF 2Or C 2～C 3The fluoro alkyl.
4. the quinazoline crotonyl compounds with general formula (I) according to claim 3, its pharmacologically acceptable salt, hydrate, prodrug or the meta-bolites that forms of metabolism in any form is characterized in that: R 1Be CHF 2, CF 2CH 3, CF 2CH 2CH 3Or CHF CHFCH 3
5. the quinazoline crotonyl compounds with general formula (I) according to claim 1 and 2, its pharmacologically acceptable salt, hydrate, prodrug or the meta-bolites that forms of metabolism in any form is characterized in that: R 2, R 3Be C independently 1～C 6Saturated hydrocarbyl.
6. the quinazoline crotonyl compounds with general formula (I) according to claim 5, its pharmacologically acceptable salt, hydrate, prodrug or the meta-bolites that forms of metabolism in any form is characterized in that: R 2, R 3Be C independently 1～C 3Saturated hydrocarbyl.
7. the quinazoline crotonyl compounds with general formula (I) according to claim 6, its pharmacologically acceptable salt, hydrate, prodrug or the meta-bolites that forms of metabolism in any form is characterized in that: R 2, R 3Be methyl, ethyl or sec.-propyl independently.
8. the quinazoline crotonyl compounds with general formula (I) according to claim 1, its pharmacologically acceptable salt, hydrate, prodrug or the meta-bolites that forms of metabolism in any form is characterized in that: shown in the structural formula as I a of described compound:
Figure FDA0000146297970000021
9. like the described quinazoline crotonyl compounds of each claim in the claim 1 to 8 with general formula (I); Its pharmacologically acceptable salt, hydrate, prodrug or in any form the meta-bolites that forms of metabolism prevent and/or treat the purposes in the medicine of the indication relevant in preparation with EGFR and HER2 kinase function.
10. purposes according to claim 9 is characterized in that: saidly comprise mammary cancer, ovarian cancer, gastrointestinal cancer, the esophageal carcinoma, lung cancer, Head and Neck squama cancer, carcinoma of the pancreas, epidermis squama cancer, prostate cancer, neurospongioma and nasopharyngeal carcinoma with EGFR and the relevant indication of HER2 kinase function.
CN201210078590.0A 2011-06-21 2012-03-23 Quinolinylcrotyl compound and its application in preparation of anti-malignant tumor drugs Active CN102838550B (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN201210078590.0A CN102838550B (en) 2011-06-21 2012-03-23 Quinolinylcrotyl compound and its application in preparation of anti-malignant tumor drugs
PCT/CN2013/072528 WO2013135176A1 (en) 2012-03-16 2013-03-13 Aminoquinazoline derivative and use thereof in preparing anti-malignant tumor medicament

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CN201110166370 2011-06-21
CN201110166370.9 2011-06-21
CN201210078590.0A CN102838550B (en) 2011-06-21 2012-03-23 Quinolinylcrotyl compound and its application in preparation of anti-malignant tumor drugs

Publications (2)

Publication Number Publication Date
CN102838550A true CN102838550A (en) 2012-12-26
CN102838550B CN102838550B (en) 2014-10-01

Family

ID=47366310

Family Applications (2)

Application Number Title Priority Date Filing Date
CN201210069348.7A Active CN102838590B (en) 2011-06-21 2012-03-16 Amino quinazoline derivative and application thereof in preparation of antineoplastic drugs
CN201210078590.0A Active CN102838550B (en) 2011-06-21 2012-03-23 Quinolinylcrotyl compound and its application in preparation of anti-malignant tumor drugs

Family Applications Before (1)

Application Number Title Priority Date Filing Date
CN201210069348.7A Active CN102838590B (en) 2011-06-21 2012-03-16 Amino quinazoline derivative and application thereof in preparation of antineoplastic drugs

Country Status (2)

Country Link
US (1) US20150065709A1 (en)
CN (2) CN102838590B (en)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103288808A (en) * 2013-05-16 2013-09-11 苏州明锐医药科技有限公司 Preparation method of afatinib (I)
WO2013135176A1 (en) * 2012-03-16 2013-09-19 苏州迈泰生物技术有限公司 Aminoquinazoline derivative and use thereof in preparing anti-malignant tumor medicament
CN104151359A (en) * 2014-07-15 2014-11-19 杭州华东医药集团新药研究院有限公司 Quinazoline compound as well as preparation method and application thereof in preparing tyrosine kinase inhibitor
CN105777656A (en) * 2014-12-25 2016-07-20 深圳海王药业有限公司 Beta crystal form of naproxen tinib tosilate, preparation method and medicine composition comprising same
CN105777655A (en) * 2014-12-25 2016-07-20 深圳海王药业有限公司 Alpha crystal form of butenamide p-toluenesulfonate, preparation method and pharmaceutical composition containing the same
CN105859641A (en) * 2015-05-05 2016-08-17 杭州华东医药集团新药研究院有限公司 Bis-maleic acid salt crystals of quinazoline crotonic compound and preparation methods and functions of bis-maleic acid salt crystals
CN106432105A (en) * 2016-08-26 2017-02-22 苏州汉酶生物技术有限公司 Chemical synthesis method of Maihuatinib (EGFR/HER2 high-efficient dual inhibitor)
CN108779079A (en) * 2016-01-06 2018-11-09 特里乌姆治疗公司 New fluorination quinazoline derivant as EGFR inhibitor
WO2020011020A1 (en) * 2018-07-10 2020-01-16 杭州华东医药集团生物医药有限公司 Mefatinib composition, related compound, preparation method therefor and use thereof
TWI847289B (en) * 2021-09-30 2024-07-01 大陸商北京賽特明強醫藥科技有限公司 Quinazoline compounds, compositions and applications thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN106146412B (en) * 2015-03-31 2019-05-24 广州市恒诺康医药科技有限公司 Quinazoline derivant and its preparation method and application
CN104774184A (en) * 2015-04-17 2015-07-15 中国药科大学 Alpha-cyano-alpha, beta-unsaturated amide compound and medical application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1867564A (en) * 2003-10-17 2006-11-22 贝林格尔·英格海姆国际有限公司 Process for preparing amino crotonyl compounds
CN1972688A (en) * 2004-05-06 2007-05-30 沃尼尔·朗伯有限责任公司 4-phenylamino-quinazolin-6-yl-amides

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6626899B2 (en) * 1999-06-25 2003-09-30 Nidus Medical, Llc Apparatus and methods for treating tissue
US6653305B2 (en) * 2000-08-26 2003-11-25 Boehringer Ingelheim Pharma Kg Bicyclic heterocycles, pharmaceutical compositions containing them, their use, and processes for preparing them
DE10063435A1 (en) * 2000-12-20 2002-07-04 Boehringer Ingelheim Pharma Chinazoline derivatives, pharmaceuticals containing these compounds, their use and process for their preparation
DE102005005505A1 (en) * 2005-02-04 2006-08-10 Boehringer Ingelheim Pharma Gmbh & Co. Kg Use of quinazoline derivatives e.g. 4-((3-chloro-4-fluoro-phenyl)amino)-6-(1-methanesulfonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, which are tyrosine kinase inhibitors, to prevent or treat symptoms of e.g. chronic rhinosinusitis
ATE552835T1 (en) * 2006-09-18 2012-04-15 Boehringer Ingelheim Int METHOD FOR TREATING TUMORS WITH EGFR MUTATIONS
CN101824029A (en) * 2009-03-05 2010-09-08 厦门艾德生物医药科技有限公司 Tyrosine kinase irreversible inhibitor and medicine composition and application thereof
US9073916B2 (en) * 2009-03-11 2015-07-07 Auckland Uniservices Limited Prodrug forms of kinase inhibitors and their use in therapy

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1867564A (en) * 2003-10-17 2006-11-22 贝林格尔·英格海姆国际有限公司 Process for preparing amino crotonyl compounds
CN1972688A (en) * 2004-05-06 2007-05-30 沃尼尔·朗伯有限责任公司 4-phenylamino-quinazolin-6-yl-amides

Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013135176A1 (en) * 2012-03-16 2013-09-19 苏州迈泰生物技术有限公司 Aminoquinazoline derivative and use thereof in preparing anti-malignant tumor medicament
CN103288808B (en) * 2013-05-16 2015-11-11 苏州明锐医药科技有限公司 A kind of Ah method is for the preparation method of Buddhist nun
CN103288808A (en) * 2013-05-16 2013-09-11 苏州明锐医药科技有限公司 Preparation method of afatinib (I)
CN107141261A (en) * 2014-07-15 2017-09-08 杭州华东医药集团新药研究院有限公司 Quinazoline compounds and preparation method thereof and the application in tyrosine kinase inhibitor is prepared
CN104151359A (en) * 2014-07-15 2014-11-19 杭州华东医药集团新药研究院有限公司 Quinazoline compound as well as preparation method and application thereof in preparing tyrosine kinase inhibitor
CN107141261B (en) * 2014-07-15 2020-05-05 杭州华东医药集团新药研究院有限公司 Quinazoline compound, preparation method thereof and application thereof in preparation of tyrosine kinase inhibitor
CN105777655B (en) * 2014-12-25 2018-02-02 深圳海王医药科技研究院有限公司 Nabumetone replaces the alpha-crystal form and preparation method and the pharmaceutical composition containing it of Buddhist nun's tosilate
CN105777655A (en) * 2014-12-25 2016-07-20 深圳海王药业有限公司 Alpha crystal form of butenamide p-toluenesulfonate, preparation method and pharmaceutical composition containing the same
CN105777656A (en) * 2014-12-25 2016-07-20 深圳海王药业有限公司 Beta crystal form of naproxen tinib tosilate, preparation method and medicine composition comprising same
CN105777656B (en) * 2014-12-25 2018-02-02 深圳海王医药科技研究院有限公司 Nabumetone replaces the beta crystal and preparation method and the pharmaceutical composition containing it of Buddhist nun's tosilate
US10065931B2 (en) 2015-05-05 2018-09-04 Hangzhou Huadong Medicine Group Biopharmaceutical Co. Ltd. Quinazolin crotyl compound dimaleate crystals and preparation methods and uses thereof
CN105859641A (en) * 2015-05-05 2016-08-17 杭州华东医药集团新药研究院有限公司 Bis-maleic acid salt crystals of quinazoline crotonic compound and preparation methods and functions of bis-maleic acid salt crystals
JP2018515508A (en) * 2015-05-05 2018-06-14 杭州華東医薬集団新薬研究院有限公司 Quinazoline rotyl compound dimaleate crystals and methods for their preparation and use
WO2016177308A1 (en) * 2015-05-05 2016-11-10 杭州华东医药集团新药研究院有限公司 Quinazolin crotyl compound dimaleate crystals and preparation methods and uses thereof
CN105859641B (en) * 2015-05-05 2018-11-16 杭州华东医药集团新药研究院有限公司 The crystal and its preparation method and application of quinazoline crotonyl compounds 2-maleate
US10640470B2 (en) 2015-05-05 2020-05-05 Hangzhou Huadong Medicine Group Biopharmaceutical Co. Ltd. Quinazolin crotyl compound dimaleate crystals and preparation methods and uses thereof
CN108779079A (en) * 2016-01-06 2018-11-09 特里乌姆治疗公司 New fluorination quinazoline derivant as EGFR inhibitor
EP3400216A4 (en) * 2016-01-06 2019-08-14 Trillium Therapeutics Inc. Novel fluorinated quinazoline derivatives as egfr inhibitors
CN106432105B (en) * 2016-08-26 2019-06-11 苏州汉酶生物技术有限公司 A kind of China advanced in years replaces the chemical synthesis process of Buddhist nun
CN106432105A (en) * 2016-08-26 2017-02-22 苏州汉酶生物技术有限公司 Chemical synthesis method of Maihuatinib (EGFR/HER2 high-efficient dual inhibitor)
WO2020011020A1 (en) * 2018-07-10 2020-01-16 杭州华东医药集团生物医药有限公司 Mefatinib composition, related compound, preparation method therefor and use thereof
TWI847289B (en) * 2021-09-30 2024-07-01 大陸商北京賽特明強醫藥科技有限公司 Quinazoline compounds, compositions and applications thereof

Also Published As

Publication number Publication date
CN102838590B (en) 2014-07-09
CN102838590A (en) 2012-12-26
US20150065709A1 (en) 2015-03-05
CN102838550B (en) 2014-10-01

Similar Documents

Publication Publication Date Title
CN102838550B (en) Quinolinylcrotyl compound and its application in preparation of anti-malignant tumor drugs
US11007197B2 (en) EGFR modulators and uses thereof
JPWO2015030021A1 (en) Pharmaceutical composition comprising pyrimidine compound as active ingredient
CN110372669A (en) A kind of compound and preparation method thereof, pharmaceutical composition and application based on the induction EGFR degradation of CRBN ligand
US10774079B2 (en) Quinazoline derivative
CN105980377B (en) Substituted pyrimidines as EGFR-T790M kinase inhibitors
WO2016023217A1 (en) Quinazoline derivative, preparation method therefor, and pharmaceutical composition and application thereof
TW200410695A (en) Quinazolinone derivatives useful as anti-hyperalgesic agents
WO2019031472A1 (en) NOVEL ANTHRANILIC ACID-BASED COMPOUND, AND Pin1 INHIBITOR, THERAPEUTIC AGENT FOR INFLAMMATORY DISEASES AND THERAPEUTIC AGENT FOR CANCER THAT USE THE SAME
CN102838539A (en) Quinolinylenamide derivative and its application in preparation of anti-malignant tumor drugs
CN101967142B (en) Thiazoleamide compound and medical application thereof in treating malignant tumor
CN112300082B (en) Phenyl piperazine quinazoline compound or pharmaceutically acceptable salt thereof, preparation method and application
WO2015021894A1 (en) Novel hydroximic acid derivative and medical application thereof
US11465986B2 (en) Crystal form of c-MET inhibitor and salt form thereof and preparation method therefor
WO2014063631A1 (en) Tyrosine kinase irreversible inhibitor and preparation method and applications thereof
CN104211682B (en) Pyridine compounds and their and application thereof
CN113444074A (en) Compound with EGFR (epidermal growth factor receptor) and Wnt dual inhibition effects as well as preparation method and application thereof
JP2022527279A (en) Quinoline derivatives and their use for the treatment of cancer
JP2017511348A (en) Inhibitor of Bcr-Abl diploid, its preparation method and its use
US20240368088A1 (en) Ep4 antagonist compound as well as salt, polymorph and use thereof
CN101175732B (en) Production method for quinazoline derivatives and its application for producing medicine used for treating tumor disease
CN105037399B (en) Bcr-Abl amphiploid inhibitor, preparation method and application thereof
WO2013135176A1 (en) Aminoquinazoline derivative and use thereof in preparing anti-malignant tumor medicament

Legal Events

Date Code Title Description
C06 Publication
PB01 Publication
C10 Entry into substantive examination
SE01 Entry into force of request for substantive examination
C14 Grant of patent or utility model
GR01 Patent grant
C41 Transfer of patent application or patent right or utility model
TR01 Transfer of patent right

Effective date of registration: 20151127

Address after: 215600 Zhangjiagang, Suzhou, Cathay Pacific North Road, building F, No., building 2, building 1

Patentee after: Metabomics Inc.

Patentee after: HANGZHOU HUADONG MEDICINE GROUP NEW MEDICINE RESEARCH INSTITUTE CO., LTD.

Patentee after: Zhongmei Huadong Pharmaceutical Co., Ltd., Hangzhou

Address before: 215600 Zhangjiagang, Suzhou, Cathay Pacific North Road, building F, No., building 2, building 1

Patentee before: Metabomics Inc.